Process to make highly substituted indenes using metal slat catalysts

ABSTRACT

The present invention is a process to make 1-aryl-2-bromo substituted indenes and 1-phenyl-2-bromo substituted indenes that can have different functional groups present around the indene ring and/or the aromatic and/or phenyl ring. The indenes are made using the corresponding 1,2-biaryl-gem-dibromocyclopropane and/or 1,2-biphenyl-gem-dibromocyclopropanes and/or 1-aryl-2-phenyl-gem-dibromocyclopropanes using a metal salts, a solvent, low temperatures.

1.0—INTRODUCTION

The following document contains some market research data concerning the recent invention disclosures. It outlines the uniqueness of each invention and some background information about the conditions, materials and compounds synthesized in the process in question. In addition relevant uses of the end products, current companies that are involved in the synthesis, sale, and manufacturing of the compounds are summarized. The following unique processes would be beneficial to customers because of the increase in efficiency, safety, and a decrease in waste by products.

2.0—Invention #1a-1b The Synthesis of Tetrahydro Isoquinolines from 2-Methyl-1-phenyl Substituted Indenes

The use of osmium tetroxide in the oxidative cleavage of the indene double bond 1 to form the corresponding keto aldehyde product 45%-65% yield (Invention 1a). This keto aldehyde 2 is then used in the reductive amination protocol with primary amines to synthesize 2,3,4-substituted tetrahydroisoquinolines 3 in 28%-99% yields (Invention b 1b). (10 examples)

2.1—Novelty and Uniqueness of Invention

1) The described process involves the synthesis of highly substituted isoquinolines (3) in high yields starting from the corresponding substituted indene (1). A process and/or protocol does not currently exist to make isoquinoline products with the substitution patterns present in the final isoquinoline.

2) The process involves the use of osmium tetroxide to cleave the indene double bond forming the keto aldehyde product (2) which is combined with the corresponding substituted amine forming the substituted isoquinoline.

3) A process does not exist to perform an oxidative cleavage on an indene scaffold using osmium.

2.2—Osmium

Osmium is a very useful catalytic metal in synthesis because of the reactions that can be performed (i.e.—Oxidative cleavage, dihydroxylations, aminohydroxylations). These reactions are used by many pharmacuetical companies and companies that synthesize building blocks for pharma (i.e.—third party synthetic contractors). The only alternative to osmium to perform an oxidative cleavage reaction involves the use of ozone which is a toxic, explosive and a hazardous gas to use. An ozone generator is needed to generate ozone for the reaction, and the reactions are not selective giving rise to many unwanted side products which leads to an increase in waste production, and a decrease in reaction efficiency.

2.3—Isoquinolines Have Biological Activity

Have many medicinal properties that allow them to be useful products for the treatment of various medical conditions. The high biological activity that isoquinolines have allows them to be attractive targets for pharma companies. There are many isoquinoline products that currently exist to be used as viable treatments.

1) Vasodilators such as papaverine are isoquinolines that are currently used pharmaceuticals.

Sold under the brand names: Pavacap, Pavadil (USA), Artegodan, Panergon (Germany), Cardiospan, Papaversan (France), Cardioverina (Countries outside Europe and US).

2) Hypertension and congestive heart failure such as quinapril.

Sold under the brand name: Accupril (Pfizer).

3) Anesthetics such as dimethisoquin.

4) Antifungal agents.

3.0—Invention #2 Process to Make Highly Substituted Indenes Using Metal Salt Catalysts

The synthesis of 2-bromo-indenes (1-4) from the corresponding 1,2-biaryl gem-dihalocyclopropanes using silver tetrafluoroborate in 1,2-dichloroethane at 65° C. The reaction involves a 2π disrotatory electrocyclic ring opening of the cyclopropyl group facilitated by the precipitation of silver bromide (AgBr) to form the 1,3-substituted allyl cation intermediate which undergoes a 4π conrotatory electrocyclic ring closing reaction to form 2-bromo-1-phenyl substituted indenes.

3.1—Novelty and Uniqueness of Invention

1) Other processes and/or protocols do not exist to synthesize highly 1,2-substituted indenes involving the use of silver salts. Other methods involve the use of very strong acids which are very hazardous due to their corrosive nature or toxic metal catalysts.

2) The process involves an electrocyclization cascade mechanism which is a very efficient high yielding reaction and never used for the synthesis of indenes.

3) The final products are part of a chemical class of indenes which have been shown to possess many desirable medicinal properties (i.e.—anticancer, insulin modulators, cardiovascular, anti obesity). They have similar core structures as in the D vitamins.

3.2—Indenes

1) Indenes are naturally occurring compounds isolated from coal tar fractions/crude oil refining

2) Main uses of indenes are for the production of indene resin which is the starting point for many plastic products (i.e., floor tiles). Also used as thermal imaging material for stenciling.

3) Indenes have been shown to possess many desirable properties and are also biologically active used as pesticides imbedded in plastic animal collars.

4) Indenes are available pharmaceuticals for the treatment of HIV (Crixivan—Merck, $275 million/2008 annual revenue) and pain (Sulindac).

3.3—Indenes That Have Biological Activity

1) Used for treatment of cerebral vascular disease—Indeloxazine (Japan).

2) Estrogen receptor agonists.

3) Selective modulators for the peroxisome proliferator activator receptor (PPAR).

4) Anti-inflammatory pharmaceutical agents—Sulindac—Clinoril—Merck US and UK.

5) Antifungal agents.

6) Used for treatment of precancerous and cancerous lesions.

7) Used as muscarinic agonists (Eli Lilly) (made via osmium catalysis)

8) Used as anticoagulants.

4.0—Invention #3 The Cross Coupling of 2-bromo-1-phenyl Indenes With Phenyl Acetylenes and Other Substituted Acetylenes in Water

This invention entails the synthesis of various cross-coupled products (20-80% yield) from the reaction between 2-bromo-1-phenyl substituted indenes with phenyl acetylene or propargyl alcohol. The reaction takes place in water in the presence of palladium chloride, triphenyl phosphine and pyrrolidine as base at 120° C.

4.1—Novelty and Uniqueness of Invention

1) There has not been any process's and/or protocol's or examples that involves the cross-coupling between an alkyne and an indene.

2) Conventional synthetic protocols that involve coupling alkynes involve the use of organic and/or halogenated solvents which from a safety standpoint are very hazardous due to their explosive nature and toxicity (i.e., carcinogenic, tetratogenic). This process offers an alternative to the use of these solvents since the reaction is performed in water which is the safest and most environmentally friendly solvents.

3) Current processes need the use of copper to regenerate the active palladium catalyst throughout the reaction. The above reaction does not involve the use of copper which is toxic. By not having to use copper, this eliminates exposure concerns during process operation. In addition, the use of copper is expensive from an industrial perspective and by eliminating the need for copper eliminates the costs associated with its use.

4.2—Alkynes

1) Alkynes are petroleum products for chemical feedstocks.

2) Alkynes are components of various rubbers and plastics.

3) Used as thermosetting resins and insulators.

4) There are alkynes that have biological activity and are used as pharmaceuticals.

5) They are primarily used as building blocks for other compounds.

4.3—Alkynes That Have Biological Activity

1) Efaviren (Sustiva) HIV inhibitor pharmacuetical.

2) Terbinafine (Lamisil, Zimig) antifungal agent.

3) Esperamicin and calicheamicin are two of the most potent antitumor agents available.

5.0—Pharmaceutical, and Generic Drug Manufacturing in Canada

Industry Government website statistics show that in Canada there are over 11 000 pharmacuetical, and chemical manufacturing companies operating and that 8000 reside in Ontario. The total revenues from this industrial sector were over $10 billion for 2009 and that imports of generic drugs and chemicals totaled over $5 billion in 2009. Ontario is a very good market to start with.

There are several companies that would use these processes to synthesize products that they use or sell:

-   -   1a) Use of osmium for the oxidative cleavage of indenes.     -   1b) Process to synthesize isoquinolines.     -   2) Process to synthesize highly substituted indenes (feedstock         chemicals for isoquinoline synthesis).     -   3) Process to cross-couple 2-bromo indenes with alkynes in water         and without copper.

5.1—Potential Customers and Target Market for the Invented Processes

The target market of the inventions would be:

-   -   1) Large pharmaceutical companies (i.e., Merck, Pfizer,         Genentech, Eli Lilly, GlaxoSmithKline).     -   2) Large chemical manufacturing companies (i.e., Dow Chemical,         Corning, Exxon).     -   3) Generic drug manufacturers (i.e., Patheon, Apotex, Dalton).     -   4) Small pharma/chemical manufacturers and specialty chemicals         (i.e., Catalent, TCI, TRC).     -   5) Government R/D facilities.     -   6) University and small contract R/D companies.

5.2—Potential Customers Located in the Greater Toronto Area

-   -   1) Large pharmaceutical companies: Glaxo Smith Kline.     -   2) Large chemical manufacturing companies: Unilever.     -   3) Generic drug manufacturing companies: Patheon, Apotex.     -   4) Small chemical manufacturers and specialty chemicals: Toronto         Research Chemicals (TRC)     -   5) University and small contract RID companies: University of         Toronto, Ryerson University, York University, McMaster         University.

6.0—Use of a Device to Perform the Processes

A microreactor flow device that has the capability of performing the above processes would be very beneficial and advantageous for the customer for several reasons:

-   -   1) A device would allow for the handling and recycling of osmium         helping to minimize costs associated with the purchasing,         storage, usage, and disposal of osmium and its corresponding         waste addressing many environmental concerns.     -   2) A device would minimize human exposure to osmium and the         corresponding waste since it is contained in the device. This is         a benefit for the customer since an added level of safety is         achieved.     -   3) These microreactor flow devices have been shown to be more         efficient than conventional batch synthesis by having the         ability to increase in reaction efficiency by minimizing waste         byproducts.     -   4) These microreactors have also been shown to allow chemical         reactions to be completed in a faster time.     -   5) These devices are usually fully automated and controlled by a         computer that allows for quick optimization of a reaction by         allowing to change variables such as temperature, flow rate,         concentration, and time.     -   6) The device is a small, compact, modular, reactor that has a         chemical output that is constant (i.e., 1 g/1 min−1 g/h). To         achieve large scale production the devices are “numbered up”         instead of “scaling up” (i.e., 1 device makes 1 g/min, therefore         after 24 h=1.44 kg, after 365 days=525.6 kg. If 50 devices were         operational then 26.2 tons of product are achieved annually).         Therefore due to the numbering up method, different synthetic         procedures are not needed on the larger scale (i.e., typically a         small batch scale synthesis (1g) differs from the large scale (1         ton) synthesis of the same product because different materials         will be needed due to potential hazards and safety         considerations associated with using a large amount of that         chemical. Usually, pharma companies have a process scale up team         that is aware of such hazards associated with these chemicals         that specializes with large production of pharmaceuticals and         chemical building blocks.). The microreactor device would not         need a process scale-up team to implement large scale production         of a drug or chemical.     -   8) The process allows for a large isoquinoline library and other         similar products to be synthesized having the ability to access         over 5 trillion isoquinoline products by varying the indene and         amine starting materials.     -   9) The process can be used for the generation of new lead         compounds, the manufacturing of generic drugs, chemical building         blocks, and their scale up.

6.1—Products and Companies That Use Microreactor Flow Technology

There are several companies that are currently using flow microreactor systems. The H-Cube is a product sold by Thales-Nano. The H-Cube allows the user to carry out hydrogenations without the need for a hydrogen tank and can handle up to half a kilogram of material/day. The unit generates hydrogen via the electrolysis of water, collects the generated hydrogen, and uses it throughout the hydrogenation. The product has been shown to be very efficient giving better results than batch methods. In addition, the lack of a tank of hydrogen eliminates any explosive hazard which is a primary concern when carrying out hydrogenations. Further, the unit is computer interfaced allowing optimal conditions to be achieved automatically (i.e., temperature, flow rate, concentration, with respect to product yield). The H-Cube retails for about $60K US and has a new larger version that is capable of higher production volumes.

There are other companies that provide microreactor systems but they are not engineered for specific processes (i.e., a specific class of reaction like hydrogenations which the H-Cube is designed for.) but rather are available as a kit for the customer to use on their current chemistry and see if it adds a benefit to them.

6.2—Companies That Use Microreactors for Their Processes

-   -   1) The top 20 largest pharmaceutical companies currently use         microreactor technology to synthesize building blocks for         pharmaceuticals (i.e., Merck, Pfizer, Genentech, etc.)     -   2) Lonza chemicals use microreactors for hydrogenations and         dehydrations.     -   3) UOP and FMC use flow reactors for hydrogen peroxide         synthesis.     -   4) Siemens-Axiva use microreactors for polyacrylamide synthesis.     -   5) Bayer-Schering use microreactors for DAST fluorinations         (methods to incorporate fluorine into a molecule) and steroid         synthesis.     -   6) Degussa chemicals use microreactors for chemical oxidations.     -   7) Xi'on Company (China) uses microreactors to synthesize         nitroglycerine.     -   8) Merck uses microreactors for synthesis (Grignard reagents).

7.0—CONCLUSION

The above inventions offer many uses and can bring value to customers because of their applicability in various chemical industries. They are unique and offer many advantages in terms of safety and efficiency. Patents on these inventions will help protect them and can aid in commercialization efforts.

PCT Application Background Information and Example Compounds

Indene synthesis and selected compounds (electrocyclization using catalysts)

Alkyne coupling and compounds

Isoquinoline synthesis and compounds

Synthesis of Highly Substituted Indenes and Derivatives Indenes and Application

-   -   1) Indenes are naturally occurring compounds isolated from coal         tar fractions/crude oil refining.     -   2) Main uses of indenes are for the production of indene resin         which is the starting point for many plastic products (i.e.,         floor tiles). Also used as thermal imaging material for         stenciling.     -   3) Indenes have been shown to possess many desirable properties         and are also biologically active used as pesticides imbedded in         plastic animal collars.     -   4) Indenes are available pharmaceuticals for the treatment of         HIV (Crixivan—Merck, $275 million/2008 annual revenue) and pain         (Sulindac).

Indenes That Have Biological Activity

-   -   1) Used for treatment of cerebral vascular disease—Indeloxazine         (Japan).     -   2) Estrogen receptor agonists.     -   3) Selective modulators for the peroxisome proliferator         activator receptor (PPAR).     -   4) Anti-inflammatory pharmaceutical         agents—Sulindac—Clinoril—Merck US and UK.     -   5) Agrochemical antifungal agents and produce coatings.     -   6) Used for treatment of precancerous and cancerous lesions.     -   7) Used as muscarinic agonists (Eli Lilly) (made via osmium         catalysis)     -   8) Used as anticoagulants.

Alkynes

-   -   1) Alkynes are petroleum products for chemical feedstocks.     -   2) Alkynes are components of various rubbers and plastics.     -   3) Used as thermosetting resins and insulators.     -   4) There are alkynes that have biological activity and are used         as pharmaceuticals.     -   5) They are primarily used as building blocks for other         compounds.

Alkynes That Have Biological Activity

-   -   1) Efaviren (Sustiva) HIV inhibitor pharmacuetical.     -   2) Terbinafine (Lamisil, Zimig) antifungal agent.     -   3) Esperamicin and calicheamicin are two of the most potent         antitumor agents available.

A B C 1

  Chemical Formula: C₁₈H₁₅ClO₂ Exact Mass: 298.08 Molecular Weight: 298.76 Elemental Analysis: C, 72.36; H, 5.06; Cl, 11.87; O, 10.7

  Chemical Formula: C₁₈H₁₅O₂ Exact Mass: 264.12 Molecular Weight: 264.32 m/z: 264.12 (100.0%), 265.12 (19.7%), 266.12 (2.3%) Elemental Analysis: C, 81.79; H, 6.10; O, 12.11

  Chemical Formula: C₁₈H₁₅NO₄ Exact Mass: 309.10 Molecular Weight: 309.32 Elemental Analysis: C, 69.89; H, 4.89; N, 4.53; O, 20.6 2

  Chemical Formula: C₁₈H₁₅ClO₂ Exact Mass: 298.08 Molecular Weight: 298.76 Elemental Analysis: C, 72.36; H, 5.06; Cl, 11.87; O, 10.7

  Chemical Formula: C₁₉H₁₈O₃ Exact Mass: 294.13 Molecular Weight: 294.34 m/z: 294.13 (100.0%), 295.13 (20.9%), 296.13 (2.6%) Elemental Analysis: C, 77.53; H, 6.16; O, 16.31

  Chemical Formula: C₁₈H₁₅NO₄ Exact Mass: 309.10 Molecular Weight: 309.32 Elemental Analysis: C, 69.89; H, 4.89; N, 4.53; O, 20.6 3

  Chemical Formula: C₁₉H₁₅NO₂ Exact Mass: 289.11 Molecular Weight: 289.33 Elemental Analysis: C, 78.87; H, 5.23; N, 4.84; O, 11.0

  Chemical Formula: C₁₉H₁₈O₃ Exact Mass: 294.13 Molecular Weight: 294.34 m/z: 294.13 (100.0%), 295.13 (20.9%), 296.13 (2.6%) Elemental Analysis: C, 77.53; H, 6.16; O, 16.31

  Chemical Formula: C₁₉H₁₅NO₂ Exact Mass: 289.11 Molecular Weight: 289.33 Elemental Analysis: C, 78.87; H, 5.23; N, 4.84; O, 11.0 4

  Chemical Formula: C₁₈H₁₅ClO₂ Exact Mass: 298.08 Molecular Weight: 298.76 Elemental Analysis: C, 72.36; H, 5.06; Cl, 11.87; O, 10.7

  Chemical Formula: C₁₉H₁₈O₃ Exact Mass: 294.13 Molecular Weight: 294.34 m/z: 294.13 (100.0%), 295.13 (20.9%), 296.13 (2.6%) Elemental Analysis: C, 77.53; H, 6.16; O, 16.31

  Chemical Formula: C₁₉H₁₅NO₂ Exact Mass: 289.11 Molecular Weight: 289.33 Elemental Analysis: C, 78.87; H, 5.23; N, 4.84; O, 11.0 5

  Chemical Formula: C₁₈H₁₅ClO₂ Exact Mass: 298.08 Molecular Weight: 298.76 Elemental Analysis: C, 72.36; H, 5.06; Cl, 11.87; O, 10.7

  Chemical Formula: C₁₉H₁₈O₃ Exact Mass: 294.13 Molecular Weight: 294.34 m/z: 294.13 (100.0%), 295.13 (20.9%), 296.13 (2.6%) Elemental Analysis: C, 77.53; H, 6.16; O, 16.31

  Chemical Formula: C₁₇H₁₅NO₃ Exact Mass: 281.11 Molecular Weight: 281.31 Elemental Analysis: C, 72.58; H, 5.37; N, 4.98; O, 17.0 6

  Chemical Formula: C₁₈H₁₅ClO₂ Exact Mass: 298.08 Molecular Weight: 298.76 Elemental Analysis: C, 72.36; H, 5.06; Cl, 11.87; O, 10.71

  Chemical Formula: C₁₈H₁₅NO₄ Exact Mass: 309.10 Molecular Weight: 309.32 Elemental Analysis: C, 69.89; H, 4.89; N, 4.53; O, 20.6

  Chemical Formula: C₁₆H₁₂ClNO₂ Exact Mass: 285.06 Molecular Weight: 285.72 Elemental Analysis: C, 67.26; H, 4.23; Cl, 12.41; N, 4.90; O, 11.20 7

  Chemical Formula: C₁₇H₁₅NO₃ Exact Mass: 281.11 Molecular Weight: 281.31 C, 72.58; H, 5.37; N, 4.98; O, 17.06

  Chemical Formula: C₁₆H₁₄ Exact Mass: 206.11 Molecular Weight: 206.28 Elemental Analysis: C, 93.16; H, 6.84

  Chemical Formula: C₁₈H₁₈O₂ Exact Mass: 266.13 Molecular Weight: 266.33 Elemental Analysis: C, 81.17; H, 6.81; O, 12.01 8

  Chemical Formula: C₁₅H₁₁Br Exact Mass: 270.00 Molecular Weight: 271.15 Elemental Analysis: C, 66.44; H, 4.09; Br, 29.4

  Chemical Formula: C₁₆H₁₃Br Exact Mass: 284.02 Molecular Weight: 285.18 Elemental Analysis: C, 67.39; H, 4.59; Br, 28.02

  Chemical Formula: C₁₇H₁₅Br Exact Mass: 298.04 Molecular Weight: 299.20 Elemental Analysis: C, 68.24; H, 5.05; Br, 26.7 9

  Chemical Formula: C₁₇H₁₅Br Exact Mass: 298.04 Molecular Weight: 299.20 Elemental Analysis: C, 68.24; H, 5.05; Br, 26.7

  Chemical Formula: C₁₅H₁₁Br Exact Mass: 270.00 Molecular Weight: 271.15 Elemental Analysis: C, 66.44; H, 4.09; Br, 29.4

  Chemical Formula: C₁₆H₁₃Br Exact Mass: 284.02 Molecular Weight: 285.18 Elemental Analysis: C, 67.39; H, 4.59; Br, 28.02 10

  Chemical Formula: C₁₆H₁₃Br Exact Mass: 284.02 Molecular Weight: 285.18 Elemental Analysis: C, 67.39; H, 4.59; Br, 28.02

  Chemical Formula: C₁₆H₁₃Br Exact Mass: 284.02 Molecular Weight: 285.18 Elemental Analysis: C, 67.39; H, 4.59; Br, 28.02

  Chemical Formula: C₁₇H₁₅Br Exact Mass: 298.04 Molecular Weight: 299.20 Elemental Analysis: C, 68.24; H, 5.05; Br, 26.7 11

  Chemical Formula: C₁₇H₁₅Br Exact Mass: 298.04 Molecular Weight: 299.20 Elemental Analysis: C, 68.24; H, 5.05; Br, 26.7

  Chemical Formula: C₁₅H₁₀BrNO₂ Exact Mass: 314.99 Molecular Weight: 316.15

  Chemical Formula: C₁₅H₁₀BrNO₂ Exact Mass: 314.99 Molecular Weight: 316.15 12

  Chemical Formula: C₁₅H₉BrCl₂ Exact Mass: 337.93 Molecular Weight: 340.04 C, 52.98; H, 2.67; Br, 23.50; Cl, 20.85

  Chemical Formula: C₁₅H₉BrCl₂ Exact Mass: 337.93 Molecular Weight: 340.04 C, 52.98; H, 2.67; Br, 23.50; Cl, 20.85

  Chemical Formula: C₁₇H₁₅Br Exact Mass: 298.04 Molecular Weight: 299.20 Elemental Analysis: C, 68.24; H, 5.05; Br, 26.7 13

  Chemical Formula: C₁₅H₉BrCl₂ Exact Mass: 337.93 Molecular Weight: 340.04 C, 52.98; H, 2.67; Br, 23.50; Cl, 20.85

  Chemical Formula: C₁₅H₉BrCl₂ Exact Mass: 337.93 Molecular Weight: 340.04 C, 52.98; H, 2.67; Br, 23.50; Cl, 20.85

  Chemical Formula: C₁₅H₁₂Cl₂ Exact Mass: 262.03 Molecular Weight: 263.16 C, 68.46; H, 4.60; Cl, 26.94 14

  Chemical Formula: C₁₅H₁₁BrCl₂ Exact Mass: 339.94 Molecular Weight: 342.06 C, 52.67; H, 3.24; Br, 23.36; Cl, 20.73

  Chemical Formula: C₁₅H₁₂Cl₂ Exact Mass: 262.03 Molecular Weight: 263.16 C, 68.46; H, 4.60; Cl, 26.94

  Chemical Formula: C₁₅H₁₄ Exact Mass: 194.11 Molecular Weight: 194.27 Elemental Analysis: C, 92.74; H, 7.26 15

  Chemical Formula: C₁₈H₁₆O₃ Exact Mass: 280.11 Molecular Weight: 280.32 C, 77.12; H, 5.75; O, 17.12

  Chemical Formula: C₁₆H₁₄O Exact Mass: 222.10 Molecular Weight: 222.28 C, 86.45; H, 6.35; O, 7.20

  Chemical Formula: C₁₆H₁₆O₂ Exact Mass: 240.12 Molecular Weight: 240.30 C, 79.97; H, 6.71; O, 13.32 16

  Chemical Formula: C₁₈H₁₈O₄ Exact Mass: 298.12 Molecular Weight: 298.33 C, 72.47; H, 6.08; O, 21.45

  Chemical Formula: C₂₃H₁₆ Exact Mass: 292.13 Molecular Weight: 292.37 C, 94.48; H, 5.52

  Chemical Formula: C₁₈H₁₄O Exact Mass: 246.10 Molecular Weight: 246.30 C, 87.78; H, 5.73; O, 6.50 17

  Chemical Formula: C₂₁H₁₆ Exact Mass: 268.13 Molecular Weight: 268.35 Elemental Analysis: C, 93.99; H, 6.01

  Chemical Formula: C₂₂H₁₈ Exact Mass: 282.14 Molecular Weight: 282.38 Elemental Analysis: C, 93.57; H, 6.43

  Chemical Formula: C₂₂H₁₈O Exact Mass: 298.14 Molecular Weight: 298.38 C, 88.56; H, 6.08; O, 5.36 18

  Chemical Formula: C₂₂H₁₈ Exact Mass: 282.14 Molecular Weight: 282.38 Elemental Analysis: C, 93.57; H, 6.43

  Chemical Formula: C₂₂H₁₈ Exact Mass: 282.14 Molecular Weight: 282.38 Elemental Analysis: C, 93.57; H, 6.43

  Chemical Formula: C₂₂H₁₈O Exact Mass: 298.14 Molecular Weight: 298.38 C, 88.56; H, 6.08; O, 5.36

Isoquinolines and Application

Have many medicinal properties that allow them to be useful products for the treatment of various medical conditions. The high biological activity that isoquinolines have allows them to be attractive targets for pharma companies. There are many isoquinoline products that currently exist to be used as viable treatments.

-   -   1) Vasodilators such as papaverine are isoquinolines that are         currently used pharmaceuticals.     -   Sold under the brand names: Pavacap, Pavadil (USA), Artegodan,         Panergon (Germany), Cardiospan, Papaversan (France),         Cardioverina (Countries outside Europe and US).     -   2) Hypertension and congestive heart failure such as quinapril.     -   Sold under the brand name: Accupril (Pfizer).     -   3) Anesthetics such as dimethisoquin.     -   4) Broad spectrum microbicides     -   5) Phosphate free surfactants and detergents.

A B C 1

  92% 98:2 Chemical Formula: C₁₇H₁₉N Exact Mass: 237.15 Molecular Weight: 237.34 C, 86.03; H, 8.07; N, 5.90

  49% 98:2 Chemical Formula: C₂₆H₂₂N₂ Exact Mass: 362.18 Molecular Weight: 362.47 C, 86.15; H, 6.12; N, 7.73 2

  62% 95:5 Chemical Formula: C₁₈H₂₁N Exact Mass: 251.17 Molecular Weight: 251.37 C, 86.01; H, 8.42; N, 5.57

  47-99% 95:5 Chemical Formula: C₂₄H₂₅N Exact Mass: 327.20 Molecular Weight: 327.46 C, 88.03; H, 7.70; N, 4.28

  73-99% 98:2 Chemical Formula: C₂₂H₂₁N Exact Mass: 299.17 Molecular Weight: 299.41 C, 88.25; H, 7.07; N, 4.68 3

  85% 98:2 Chemical Formula: C₂₀H₂₅N Exact Mass: 279.20 Molecular Weight: 279.42 C, 85.97; H, 9.02; N, 5.01

  75% 98:2 Chemical Formula: C₂₃H₂₃N Exact Mass: 329.18 Molecular Weight: 329.43 C, 83.85; H, 7.04; N, 4.25; O, 4.86

  72% 90:10 Chemical Formula: C₂₂H₂₀FN Exact Mass: 317.16 Molecular Weight: 317.40 C, 83.25; H, 6.35; F, 5.99; N, 4.41 4

  72% 95:5 Chemical Formula: C₂₃H₂₃N Exact Mass: 313.18 Molecular Weight: 313.44 C, 88.13; H, 7.40; N, 4.47

  28% 70:30 Chemical Formula: C₂₂H₂₀N₂O₂ Exact Mass: 344.15 Molecular Weight: 344.41 C, 76.72; H, 5.85; N, 8.13; O, 9.29 

1. A chemical process (FIGS. 1 and 2) that involves the use of a solvent, 1,2-biaryl gem-dibromocyclopropane, and a metal salt or other salt at low temperatures to make to make 1-phenyl-2-bromo indenes in a vessel that is capable of being closed.
 2. The 1,2-biaryl gem-dibromocyclopropane is synthesized from stilbene but is not limited to.
 3. The 1,2-biaryl gem-dibromocyclopropane contains on either of the aryl ring a functional group such as chloro (—Cl), nitro (—NO₂), methyl (-Me), but is not limited to these functional groups (for example —H) and their positioning around the aryl ring (for example the ortho, meta, and para, positions and any combination).
 4. The metal salt in claim 1 is a silver tetrafluoroborate salt but is not limited to.
 5. The metal salt in claim 1 can be a triphenyl carbenium cation and its salts and/or derivatives but is not limited to.
 6. The solvent in claim 1,2,3,4 is 1,2-dichloroethane but is not limited to.
 7. The temperature in claim 1 for the process is within the range of 0° C.-100° C.
 8. The process in claim 1 can form 1-phenyl-2-bromo indenes selectively using 1,2-biaryl-gem-dibromocyclopropanes and 1,2-biphenyl-gem-dibromocyclopropanes efficiently in chemical yields ranging from 0.0000001%-99.999999% but not limited to these yields.
 9. The process in claim 1 involves a 2 pi electrocyclic ring opening followed by a 4 pi electrocyclic ring closing reaction to form an indene of different substitution patterns (FIG. 3).
 10. The process in claim 1 can obtain 1-phenyl-2-bromo substituted indenes with high purities in under 30 minutes at 65° C. but not limited to this time and temperature.
 11. In one embodiment, other processes and/or protocols do not exist to synthesize 1,2-substituted indenes involving the use of silver salts. Other methods involve the use of very strong acids which are very hazardous due to their corrosive nature or toxic catalysts. This process does not use toxic catalysts and/or corrosive acids to form indenes.
 12. The final products are part of a chemical class of indenes which have been shown to possess many desirable medicinal properties (i.e.—anticancer, insulin modulators, cardiovascular, anti-obesity treatments, treatment of HIV infection).
 13. The reaction vessel in claim 1 can be any vessel that is capable of being sealed but not limited to a vessel.
 14. The reaction vessel in claim 1 can be a microreactor and/or flow apparatus bearing a design engineering functionality consisting of pre-fabricated channels and/or grooves with dimensions ranging from 1 nanometer to 200 micrometers but not limited to these dimensions.
 15. The reaction vessel in claim 1 can have the chemical reaction fluid passing inside the inner channels and/or grooves with distances travelled by the reaction fluid ranging from 1 fm to 1000 meters but not limited to these dimensions or combinations thereof.
 16. The reaction vessel in claim 1 can be capable of obtaining temperature ranges from −150° C. to 1000° C. but not limited to these ranges.
 17. The reaction vessel in claim 1 can be capable of altering and/or regulating the rate of reaction fluid flow and the residence times within the prefabricated channels and/or grooves.
 18. The residence times of the reaction vessel in claims 1 and 14 can be within the ranges of 0.0001 mL/minute-500 L/min but not limited to these ranges. 